Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib

Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., Louis, D. N., Christiani, D. C., Settleman, J., Haber, D. A. (May 2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England Journal of Medicine, 350 (21). pp. 2129-39. ISSN 1533-4406 (Electronic)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/15118073
DOI: 10.1056/NEJMoa040938

Abstract

BACKGROUND: Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS: We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS: Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.

Item Type: Paper
Uncontrolled Keywords: Adenocarcinoma drug therapy genetics Adult Aged Aged, 80 and over Amino Acid Sequence Antineoplastic Agents therapeutic use Base Sequence Carcinoma, Non-Small-Cell Lung drug therapy genetics DNA Mutational Analysis Drug Resistance Neoplasm genetics Epidermal Growth Factor metabolism Female Genes erbB-1 Heterozygote Humans Lung Neoplasms drug therapy genetics Male Middle Aged Molecular Sequence Data Mutation Protein-Tyrosine Kinases antagonists & inhibitors/genetics metabolism Quinazolines therapeutic use Receptor Epidermal Growth Factor chemistry genetics metabolism Sequence Deletion
Subjects: diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
therapies
diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > EGFR
diseases & disorders > cancer > cancer types > lung cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
diseases & disorders > cancer > cancer types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Sordella lab
Depositing User: CSHL Librarian
Date: 20 May 2004
Date Deposited: 01 Feb 2012 14:48
Last Modified: 13 Mar 2013 16:10
Related URLs:
URI: http://repository.cshl.edu/id/eprint/22429

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